1. Field of the Invention
The present invention relates to an improved process for preparing 2-haloacyl-3-aminoacrylic acid derivatives and pyrazole-4-carboxylic acid derivatives obtainable from them.
2. Brief Description of the Prior Art
2-Haloacyl-3-aminoacrylic acid derivatives, for example 2-trifluoroacetyl-3-aminoacrylic esters, are valuable intermediates in preparing substituted pyrazoles which find use as fungicides, pesticides and herbicides.
EP-A 1 000 926 discloses a process for preparing 2-trihaloacetyl-3-amino-acrylic esters by substituting trihaloacetyl acetates using orthoformic acid derivatives. However, the yields of the reaction obtained are only 61.8% and unacceptable for industrial use.
A further method for preparing such compounds is described by Bartnik et al. (Tetrahedron Lett. (1996), 37(48), 8751-8754). xcex2-Chloroacroleins are reacted with secondary amines in diethyl ether at room temperature (RT) in yields of from 44 to 84%.
GHowever, a disadvantage of this process is that the chloroacroleins used as starting compounds are difficult to prepare and accordingly too expensive for industrial use.
There is accordingly a need to develop an improved process for preparing 2-haloacyl-3-aminoacrylic acid derivatives starting from easily obtainable reactants.
A process for preparing 2-haloacyl-3-aminoacrylic esters has now been found which is characterized in that
a) N-substituted 3-aminoacrylic esters are reacted with haloalkylcarboxylic anhydrides in the presence of base and optionally in the presence of solvent.
If desired, the 2-haloacyl-3-aminoacrylic esters obtained in this manner may be
b) converted by reaction with hydrazines to 3-haloalkyl-4-pyrazolecarboxylic esters which
c) may be reacted further by acid or alkali hydrolysis to give 3-haloalkyl-4-pyrazolecarboxylic acids.
For the purposes of the invention, exemplary and preferred 3-aminoacrylic esters used are of the general formula (I) 
where
R1 is C1-C12-alkyl, C6-C18-aryl or C7-C19-arylalkyl and
R2 and R3 are each independently C1-C12-alkyl or C7-C19-arylalkyl.
Preference is given to R1 being C1-C4-alkyl, more preferably methyl or ethyl, and to R2 and R3 each independently being C1-C4-alkyl, more preferably methyl or ethyl.
Particularly preferred 3-aminoacrylic esters of the general formula (I) are methyl 3-(N,N-dimethylamino)acrylate and methyl 3-(N,N-diethylamino)-acrylate, and methyl 3-(N,N-dimethylamino)acrylate is even more preferred.
The 3-aminoacrylic esters to be used can be prepared according to the literature or in a similar manner (EP-A 608 725).
For the purposes of the invention, alkyl is a straight-chain, cyclic, branched or unbranched alkyl radical which may optionally be further substituted by C1-C6-alkoxy radicals, for example methoxy or ethoxy. The same applies to the alkylene moiety of an arylalkyl radical.
For example, C1-C4-alkyl is methyl, ethyl, ethoxyethyl, n-propyl, isopropyl, n-butyl ortert-butyl, C1-C8-alkyl is also n-pentyl, cyclohexyl, n-hexyl, n-octyl or isooctyl, and C1-C12-alkyl is also, for example, n-decyl or n-dodecyl.
For the purposes of the invention, alkoxy is a straight-chain, cyclic, branched or unbranched alkoxy radical which may optionally be further substituted by C1-C6-alkoxy radicals, for example methoxy or ethoxy.
For example, C1-C6-alkoxy is methoxy, ethoxy, 2-ethoxyethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy or cyclohexyloxy.
For the purposes of the invention, exemplary and preferred aryl radicals are carbocyclic aromatic radicals having from 6 to 18 skeleton carbon atoms (C6-C18-aryl), for example phenyl or naphthyl.
The carbocyclic aromatic radicals may be further substituted by up to five identical or different substituents per cycle, for example those selected from the group of chlorine, fluorine, nitro, cyano, C1-C4-alkyl, for example methyl or ethyl, C1-C4-acyl, for example acetyl, C1-C4-alkoxy, for example methoxy or ethoxy, C6-C12-aryl, for example phenyl, C7-C13-arylalkyl, for example benzyl, or C6-C12-aryloxy, for example phenoxy.
Examples of C6-C10-aryl radicals include phenyl, o-, m- and p-tolyl, o-, m- and p-anisyl and naphthyl, and examples of C6-C18-aryl also include, for example, anthracenyl.
The same applies to the aryl moiety of an arylalkyl radical. C7-C13-Arylalkyl is, for example, benzyl or the isomeric 1-methylbenzyls, and C7-C13-arylalkyl is also, for example, fluorenyl.
In step a) of the process according to the invention, haloalkylcarboxylic anhydrides are used.
For the purposes of the invention, haloalkylcarboxylic anhydrides are not only symmetric anhydrides or mixed anhydrides of different haloalkylcarboxylic acids, but also mixed anhydrides of haloalkylcarboxylic acids with organic acids, for example sulphonic acids, or inorganic acids, for example hydrohalic acids. The latter are frequently also termed haloalkylcarbonyl halides.
Exemplary and preferred haloalkylcarboxylic anhydrides are of the general formula (IIa) 
where
X is chlorine, bromine or iodine, preferably chlorine and
Hal are each independently chlorine or fluorine, preferably fluorine and
R4 is chlorine, fluorine or C1-C12-haloalkyl, C1-C12-alkyl, C6-C18-aryl or C6-C19-arylalkyl, preferably chlorine, fluorine, trifluoromethyl, pentafluoroethyl, nonafluorobutyl or C1-C4-alkyl, more preferably fluorine.
Further exemplary and preferred haloalkylcarboxylic anhydrides are of the general formula (IIb) 
where
Hal and the R4 radicals are each as defined and subject to the same preferences as stated under the general formula (IIa).
Preference is given to the R4 radicals in the general formula (IIb) being identical.
For the purposes of the invention, exemplary and preferred haloalkyl radicals are branched or unbranched, open-chain or cyclic alkyl radicals which may be singly, multiply or fully substituted by halogen atoms selected from the group of chlorine and fluorine.
Exemplary and preferred C1-C12-haloalkyl radicals are trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and nonafluorobutyl.
Exemplary and preferred haloalkylcarboxylic anhydrides are trifluoroacetic anhydride, trifluoroacetyl chloride, trichloroacetic anhydride and trichloroacetyl chloride.
The molar ratio of haloalkylcarboxylic anhydrides to 3-aminoacrylic esters used may be, for example, from 0.3 to 1.5, preferably from 0.8 to 1.1 and more preferably from 0.95 to 1.05.
Exemplary and preferred bases are tertiary nitrogen bases, carbonates and hydrides.
Particular preference is given to using tertiary nitrogen bases, for example tertiary amines, substituted or unsubstituted pyridines and substituted or unsubstituted quinolines.
Very particular preference is given to using pyridine, 2-, 3-, 4-picoline, 2,6-lutidine and quinoline bases, and bases of the general formula (IIIa)
NR5R6R7xe2x80x83xe2x80x83(IIIa)
where R5, R6 and R7 are each independently C1-C16-alkyl, C7-C19-arylalkyl or C6-C18-aryl, or two radicals together may also form part of a 5- to 8-membered N-heterocyclic radical, or all three radicals together may form part of an N-heterobicyclic or N-heterotricyclic radical having from 5 to 9 ring atoms per cycle which may also contain other heteroatoms, for example oxygen.
Preference is likewise given to using bases of the general formula (IIIb)
R8R9xe2x80x94Nxe2x80x94Axe2x80x94NR10R11xe2x80x83xe2x80x83(IIIb)
where
A is C2-C8-alkylene, preferably, for example, 1,2-ethylene, 1,3-propylene, 2,3-butylene, 1,2-cyclohexylene or C6-C18-arylenes, for example 1,2-phenylene and
the R8, R9, R10 and R11 radicals are each independently
C1-C18-alkyl, C7-C19-arylalkyl or C6-C18-aryl or two radicals together may also form part of a 5- to 8-membered N-heterocyclic ring or may form a bridge between the two nitrogen atoms or all four radicals together may form part of a bis-N-heterobicyclic or bis-N-heterotricyclic radical having from 5 to 9 ring atoms per cycle which may also contain heteroatoms, for example oxygen.
Preferred examples of bases of the general formula (IIIa) are trimethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-ethylcyclohexylamine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, N-ethylmorpholine, dimethylhexadecylamine and N,N-dimethylbenzylamine.
Equally preferred examples of bases of the general formula (IIIb) are N,N,N,N-tetramethylethylenediamine, N,N-dimethyl-1,4-diazacyclohexane, N,N-diethyl-1,4-diazacyclohexane, 1,8-bis-(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN) and diazabicycloundecane (DBU).
Very particular preference is given to using triethylamine as base.
The molar ratio of base to haloalkylcarboxylic anhydrides used may be, for example, from 0.3 to 3, preferably from 1.0 to 2.0 and more preferably from 1.05 to 1.5.
The use of larger quantities of base is not critical but uneconomical.
The reaction of the 3-aminoacrylic esters with haloalkylcarboxylic anhydrides in the presence of base may be carried out at temperatures of, for example, from xe2x88x9230 to 120xc2x0 C., preferably from xe2x88x9210 to 20xc2x0 C.
Preference is given to carrying out the reaction in the presence of solvent.
Examples of useful solvents include aliphatic or aromatic hydrocarbons which may further be substituted by fluorine and chlorine atoms, and ethers, for example THF or dioxane.
Exemplary and preferred solvents include toluene, o-, m-, p-xylene, chlorobenzene, fluorobenzene, the isomeric chlorofluorobenzenes, dichloromethane, n-hexane, cyclohexane, methylcyclohexane, heptane, octane, isooctane, petroleum ether, petroleum fractions, THF and dioxane, and particular preference is given to toluene.
The solvent can be used in a quantity of, for example, 50 to 1000 ml of solvent per mole of 3-aminoacrylic acid derivative. This quantity is preferably from 100 to 600 ml. Larger solvent quantities are not critical, but uneconomical.
The process according to the invention may be, for example, to initially charge the base and haloalkylcarboxylic anhydride in a solvent and add the 3-aminoacrylic acid derivative.
In a preferred embodiment of the process according to the invention, the 3-amino-acrylic acid derivative and base are initially charged in a solvent and the haloalkylcarboxylic anhydride is added.
The workup procedure may be, for example, to remove any precipitated salts, for example by filtration, centrifugation or sedimentation and decantation, and to either directly further react the reaction solution obtained in this manner or concentrate it, for example to dryness, to obtain the 2-haloacyl-3-aminoacrylic ester.
The 2-haloacyl-3-aminoacrylic acid derivatives may optionally be further purified by distillation, but this is unnecessary for use for preparing 3-haloalkyl-4-pyrazolecarboxylic esters.
According to the invention, the exemplary and preferred 2-haloacyl-3-aminoacrylic esters obtained are of the general formula (IV) 
where
Hal and R4 are each as defined and subject to the same preferences as stated under the general formula (IIa) and
R2 and R3 radicals are each as defined and subject to the same preferences as stated under the general formula (I).
Preferred compounds of the general formula (IV) include:
methyl 3-N,N-dimethylamino-2-trifluoroacetylacrylate,
ethyl 3-N,N-diethylamino-2-trifluoroacetylacrylate,
methyl 3-N,N-dimethylamino-2-trichloroacetylacrylate,
ethyl 3-N,N-diethylamino-2-trichloroacetylacrylate,
ethyl 3-N,N-dimethylamino-2-trichloroacetylacrylate,
methyl 3-N,N-diethylamino-2-trichloroacetylacrylate,
ethyl 3-N,N-dimethylamino-2-trifluoroacetylacrylate and
ethyl 3-N,N-diethylamino-2-trifluoroacetylacrylate.
The 2-haloacyl-3-aminoacrylic acid derivatives prepared according to the invention are suitable in particular for preparing 3-haloalkyl-4-pyrazolecarboxylic esters (step b).
The 2-haloacyl-3-aminoacrylic esters of the general formula (IV) can exemplarily and preferably be reacted with hydrazines of the general formula (V), optionally in the presence of solvents, to convert them to 3-haloalkyl-4-pyrazolecarboxylic esters of the general formula (VI). 
In the general formula (V), R12 is exemplarily and preferably hydrogen, C1-C12-alkyl, C6-C18-aryl or C7-C19-arylalkyl, more preferably C1-C4-alkyl. Very particular preference is given to using hydrazine, methylhydrazine and ethylhydrazine, and methylhydrazine is even more preferred.
In the formula (VI) 
R1 is as defined and subject to the same preferences as stated under the general formula (I) and
Hal and R4 are each as defined and subject to the same preferences as stated under the general formula (IIa) and
R12 is as defined and subject to the same preferences as stated under the general formula (V).
Preferred compounds of the general formula (VI) include:
methyl 1-methyl-3-trifluoromethyl-4-pyrazolecarboxylate,
ethyl 1-methyl-3-trifluoromethyl-4-pyrazolecarboxylate,
methyl 1-methyl-3-trichloromethyl-4-pyrazolecarboxylate and
ethyl 1-methyl-3-trichloromethyl-4-pyrazolecarboxylate.
Preference is given to carrying out the reaction in the presence of solvent. Exemplary and preferred solvents are those cited above for carrying out step a).
In a particularly preferred embodiment of the process according to the invention, the compounds of the general formula (VI) are prepared using the solution from step a), optionally after removal of solids.
The reaction with hydrazine can exemplarily and preferably be effected at xe2x88x9230 to +80xc2x0 C., particularly preferred at xe2x88x9220 to 25xc2x0 C. and most preferably at xe2x88x9210 to 10xc2x0 C.
The 3-haloalkyl-4-pyrazolecarboxylic acid derivatives may, if desired, be converted in a manner known per se (Houben-Weyl, Methoden der organischen Chemie, 4th edition, Volume E5, p 223ff.), for example by acid or alkaline hydrolysis, to 3-haloalkyl-4-pyrazolecarboxylic acids of the general formula (VII) 
where
Hal and R4 are each as defined and subject to the same preferences as stated under the general formula (IIa) and
R12 is independently as defined and subject to the same preferences as stated under the general formula (V) and M, in the case of alkaline hydrolysis, is the cation of the base used, or, after acidification or in the case of acid hydrolysis, is hydrogen.
Preference is given to alkaline hydrolysis. This may be affected in a manner known per se, for example by reaction with bases, for example alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or the aqueous solutions thereof. Examples of useful solvents include water, alcohols, for example methanol, ethanol and isopropanol, aromatic hydrocarbons, for example toluene, acetone or pyridine, or mixtures of such solvents.
In a preferred embodiment of the process according to the invention, the compounds of the general formula (VII) are prepared using the reaction solution from step b).
In a particularly preferred embodiment of the process according to the invention, the compounds of the general formula (VII) are prepared by carrying out steps a), b) and c) without intermediate isolation in the same solvent, preferably aromatic hydrocarbons, for example toluene.
Preferred compounds of the general formula (VII) are:
1-methyl-3-trifluoromethyl-4-pyrazolecarboxylic acid, 3-trifluoromethyl-4-pyrazolecarboxylic acid and 3-trichloromethyl-4-pyrazolecarboxylic acid.
The 2-haloacyl-3-aminoacrylic esters, 2-haloacyl-3-aminoacrylic esters and pyrazole-4-carboxylic acids or salts thereof prepared according to the invention are particularly suitable for the application in a process for preparing pharmaceuticals and agrochemicals, for example fungicides, pesticides and herbicides.
The process according to the invention has the advantage that 2-haloacyl-3-amino-acrylic esters can be prepared from easily obtainable substances in yields of over 95%.
A further advantage of the process according to the invention is that substituted pyrazole-4-carboxylic esters or acids, optionally in the form of their salts, can be obtained without isolating the 2-haloacyl-3-aminoacrylic esters and without changing the solvent.